The Heart of the Matter – Musings on Monitors

Ask a study monitor why they do what they do, and they’ll quickly tell you that they love being involved in clinical research. Then, they’ll usually add that they were lured by the money, the flexibility, and the variety. While one or more of these reasons may prompt someone to become a monitor, their success in the field depends on an entirely different set of factors. Some of the necessary skills can be learned in school, especially if the course of study was in one of the physical sciences. Other skills can be taught as part of the new monitor’s onboarding and at individual study training sessions. However, of equal and perhaps greater importance are the individual’s personal commitment to excellence and the amount of actual field experience. Those are the factors that distinguish great monitors from all of the rest.

Clinical study monitors are representatives of the study sponsor and, as such, are responsible for ensuring that the study is conducted in exact compliance with the protocol, that all study activities conform to Good Clinical Practice (GCP) guidelines (VICH GL 9, available at http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/ucm052417.pdf), and that all other regulatory requirements are met. The study monitor oversees the performance of each investigator, assists site personnel, ensures the authenticity and integrity of all study data, and serves as the principal liaison for all communications between the study sites and the sponsor. If they have done their job well, there will be few, if any, surprises when the final study data are submitted to the sponsor or if one of their sites is audited by the regulatory agency.

Finding Study Monitors
According to VICH, section 5.1, “The monitor should have scientific training and experience to knowledgeably oversee a particular study. The monitor should be trained in quality control techniques and data verification procedures. The monitor should understand all applicable protocol requirements and be able to determine whether the study was conducted in accordance with the protocol and relevant SOPs.”

Finding a good study monitor is no different from finding a good candidate for any other position. Deciding what to look for is easy: aptitude, education, experience, and commitment. Assessing an individual candidate against those four parameters, though, can be challenging.

Does the candidate have the innate ability to absorb new material? Do they have formal education in a scientific field?

Some sponsors look for at least a baccalaureate degree in one of the life sciences to demonstrate basic understanding and familiarity with medical terminology. Do they have relevant past experience (laboratory research, academic or private practice veterinary hospital, human clinical research)? Do their track record and/or references indicate a commitment to success? In today’s environment of employee privacy, it may be difficult to obtain reliable references beyond basic employment information. Can they work well with a wide diversity of people? Have they demonstrated an ability to solve problems and meet deadlines? The higher a candidate scores on these and other factors will determine the likelihood of superior performance in the field…after onboarding and study-specific training!

Training Study Monitors
As with any new employee, a new study monitor first should be introduced to company policies and procedures. They then should be trained in their new company’s standard operating procedures for conducting clinical research. Some companies give the new monitor the protocol from a previous study and selected site data to review, and then use the results as a guide for further training. Others assign the new monitor to “shadow” an experienced monitor to gain some supervised experience before being sent out on their own. Some companies also give the new monitor a detailed checklist and then test their understanding of that checklist while role-playing a site visit. Whichever method or combination of methods is used, the goal is to prepare the new monitor to attend study-specific protocol training and then to successfully monitor investigative sites under that protocol.

Monitoring Activities
Clinical study monitors have three principal responsibilities. First and foremost is the review of study data and documentation from each of the investigative sites, as well as the issuance and resolution of queries regarding any data that are missing, out of the protocol’s acceptable range, inconsistent with other data, incorrect, improperly formatted, or otherwise requiring clarification or further action (e.g., reporting of adverse events).

The monitor’s second principal responsibility is to document, review, and catalogue all study communications, whether verbal, written, or electronic. All study-related conversations, telephone calls, emails, faxes, reports, notices, correspondence, and file notes must be retained as part of the study’s permanent record. This record tells the story behind the data, much as a libretto supports an opera, and is a necessary component of a successful study.

The monitor’s third principal responsibility is to oversee the study activities at each of their assigned investigative sites and to periodically visit each site to confirm that their performance complies in all respects with the protocol’s requirements. The frequency of site monitoring visits will be determined through a combination of the sponsor’s initial monitoring plan, the complexity of the study, the pace of enrollment at each site, and the performance of each investigator as indicated by the quality of their data, the number and type of protocol deviations, and the number and type of queries.

There are four principal types of site monitoring visits: site qualification visits, site initiation visits, interim site monitoring visits, and site close-out visits. Following the completion of each site visit, the study monitor should file a report documenting their activities during the site visit, their findings, instructions given to the investigator and/or site personnel, and any follow-up action that may be required.

The purpose of a site qualification visit is to determine whether (a) the investigator and participating clinic staff are sufficiently capable and motivated to complete their study activities in accordance with the protocol, GCPs, and all regulatory requirements, and (b) the clinic is adequately staffed, well organized, and equipped with the necessary technology, supplies, and properly-calibrated equipment to successfully complete the study. During this visit, the monitor also will detail the investigator’s responsibilities that are included in VICH GL 9, Section 3 and assess their understanding of the protocol. They also will review the clinic’s standard operating procedures to ensure that they will support superior study performance. Lastly, the monitor will inspect the clinic’s medical records and, depending on the targeted indication, confirm that the clinic has a sufficient patient population with the target indication to enable prompt enrollment of the required number of study subjects.

The site initiation visit allows the study monitor to evaluate the investigator’s understanding of all of the material presented during study training, to reconfirm their availability for the duration of the study, and to verify that the correct amount of test article and any necessary supplies have been delivered and are properly stored. Monitors often find it beneficial to review the protocol’s schedule of activities, enrollment criteria, test article accounting, and other study details with the investigator and participating site personnel to ensure that everyone is very clear on their responsibilities, procedures to be followed, and required documentation. The monitor also should review the process for reporting and documenting protocol deviations and adverse events.

If possible, some monitors schedule their site initiation visits to coincide with each site’s first enrollment or, when that is not feasible, to occur before additional study subjects are enrolled. This format provides an excellent opportunity to observe the investigator and participating site personnel under actual study conditions and to determine whether remedial training is warranted. It also gives the study monitor a chance to assess the site’s recruitment strategy and project if and when the site might meet its enrollment quota. After study training, the site initiation visit is a key determinant of site performance. Additional time spent at this early stage of the study will pay big dividends later on.

Interim site monitoring visits are periodic check-ups on each site’s performance. They are scheduled according to a monitoring plan approved by the sponsor prior to the start of the study. However, individual site results may dictate additional visits to address a problem or fewer visits at low enrolling sites or those with minimal queries. In addition, sites with successful past performance may receive fewer interim monitoring visits than newer, less experienced sites. During each interim site monitoring visit, the study monitor verifies protocol compliance, reconciles test article inventory, and reviews all required study documentation. They also review each study subject’s medical record to ensure compliance with the protocol’s inclusion/exclusion criteria and check for data entry discrepancies. For studies employing electronic data capture (EDC), the monitoring plan may allow for some interim site monitoring visit activities to be completed remotely. In those instances, the study monitor can review site data in real time through the EDC system, and then issue and resolve queries electronically. However, there is no substitute for hands-on verification to ensure that all of the protocol’s requirements are being met. Therefore, the study monitor should complete at least one interim site monitoring visit at each site.

A site close-out visit is scheduled after the last subject enrolled at each site has completed its last study visit. During the close-out visit, the study monitor will resolve any outstanding data queries, confirm that the site’s study binder is properly organized with all required documents, and instruct the investigator and participating site personnel in their ongoing study responsibilities for document and data retention. The monitor then will make certified copies of any documentation that must be retained by the site and pack all document originals for shipment to the sponsor. The monitor also will perform a final reconciliation of the test article inventory and review the documented resolution of any discrepancies. In most instances, the monitor will assist site personnel with the packaging and return of test article to the sponsor and with the return or destruction of laboratory kits and supplies. Before leaving the site, the study monitor will discuss audit readiness and review the procedures to be followed should the site receive notice of a pending FDA site audit.

Comprehensive training can prepare a new study monitor to perform all of their responsibilities, and time invested in such training will reap rewards once the monitor is assigned to an actual study and travels to sites in the field. However, truly exceptional performance is rare until a new monitor’s skills have been honed by years of experience.

Bonus: Ten Tips for Masterful Monitoring

  1. Before a study starts, introduce the assigned monitor to each site’s staff to ensure that everyone is compatible and committed to superior results. Monitor-site staff rapport is essential to successful site performance.
  2. Assign only full-time monitors and, to the extent possible, allow only participating site personnel who are available for the duration of the study.
  3. Review the protocol and case report forms with all assigned and back-up monitors before the investigator training meeting to uncover any potential problems or bottlenecks and to clarify and reinforce monitor responsibilities.
  4. Establish a monitoring communication plan which details what needs to be communicated, by whom, to whom, and when. Whenever possible, create communication templates to standardize documentation. Keep the sponsor informed at all times about all issues.
  5. Establish a monitoring team conference-call schedule to review the results of each monitoring visit (qualification, initiation, interim, and close-out) so monitors can share experience and collaborate on problem solutions.
  6. Develop a monitoring visit schedule for each site, tailored to their clinical trial experience, familiarity with the study’s target indication, and projected enrollment. Some sites may warrant more visits than others, depending on their respective enrollment pace, number of protocol deviations, data quality, and query volume.
  7. Create an enrollment timeline by site and report site enrollment status weekly. Before the study starts, plan enrollment enhancement strategies for those sites which lag behind their timeline.
  8. Establish and maintain study data review schedules, whether data are collected via paper case report forms or an electronic data capture system. Review data forms and issue queries promptly to catch protocol deviations and adverse events as soon as possible and to identify sites needing remedial training.
  9. Before the study starts, develop a proactive inventory control plan to prevent discrepancies from occurring. Reconcile test article inventory on a regular schedule, but no less frequently than every monitoring visit. Resolve discrepancies immediately and quickly report any unresolved discrepancies to the sponsor.
  10. Role-play various study and site visit scenarios to anticipate problems, develop preventive measures, and plan courses of corrective action. Identify resources that may be needed and determine their cost and availability.

In many ways, clinical study monitors are like traffic cops. They keep the study moving, look out for problems, give instruction where needed, assist at and report on “accidents,” and stop those who don’t follow the “rules of the road.” They ensure that all study data and required documentation are complete, consistent, and accurate, thereby playing a crucial role in the approval process for new therapies which improve the health and wellbeing of all animals. And that is the heart of the matter.